Details of a Researcher - YOKOTA Shinichi

Papers - YOKOTA Shinichi

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Pathogenic Lineage of mcr-Negative Colistin-Resistant Escherichia coli, Japan, 2008-2015

Toyotaka Sato, Akira Fukuda, Yuuki Suzuki, Tsukasa Shiraishi, Hiroyuki Honda, Masaaki Shinagawa, Soh Yamamoto, Noriko Ogasawara, Masaru Usui, Hiroki Takahashi, Satoshi Takahashi, Yutaka Tamura, Shin-ichi Yokota

EMERGING INFECTIOUS DISEASES ( CENTERS DISEASE CONTROL ) 22 ( 12 ) 2223 - 2225 2016.12 [Refereed]

DOI

Clarithromycin prevents human respiratory syncytial virus-induced airway epithelial responses by modulating activation of interferon regulatory factor-3

Keisuke Yamamoto, Soh Yamamoto, Noriko Ogasawara, Kenichi Takano, Tsukasa Shiraishi, Toyotaka Sato, Ryo Miyata, Takuya Kakuki, Ryuta Kamekura, Takashi Kojima, Hiroyuki Tsutsumi, Tetsuo Himi, Shin-ichi Yokota

PHARMACOLOGICAL RESEARCH ( ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD ) 111 804 - 814 2016.09 [Refereed]

Macrolide antibiotics exert immunomodulatory activity by reducing pro-inflammatory cytokine production by airway epithelial cells, fibroblasts, vascular endothelial cells, and immune cells. However, the underlying mechanism of action remains unclear. Here, we examined the effect of clarithromycin (CAM) on pro-inflammatory cytokine production, including interferons (IFNs), by primary human nasal epithelial cells and lung epithelial cell lines (A549 and BEAS-2B cells) after stimulation by Toll-like receptor (TLR) and RIG-I-like receptor (RLR) agonists and after infection by human respiratory syncytial virus (RSV). CAM treatment led to a significant reduction in poly I:C-and RSV-mediated IL-8, CCL5, IFN-beta and -lambda production. Furthermore, IFN-beta promoter activity (activated by poly I:C and RSV infection) was significantly reduced after treatment with CAM. CAM also inhibited IRF-3 dimerization and subsequent translocation to the nucleus. We conclude that CAM acts a crucial modulator of the innate immune response, particularly IFN production, by modulating IRF-3 dimerization and subsequent translocation to the nucleus of airway epithelial cells. This newly identified immunomodulatory action of CAM will facilitate the discovery of new macrolides with an anti-inflammatory role. (C) 2016 Elsevier Ltd. All rights reserved.

DOI

Mumps Virus Induces Protein-Kinase-R-Dependent Stress Granules, Partly Suppressing Type III Interferon Production

Shin Hashimoto, Soh Yamamoto, Noriko Ogasawara, Toyotaka Sato, Keisuke Yamamoto, Hiroshi Katoh, Toru Kubota, Tsukasa Shiraishi, Takashi Kojima, Tetsuo Himi, Hiroyuki Tsutsumi, Shin-ichi Yokota

PLOS ONE ( PUBLIC LIBRARY SCIENCE ) 11 ( 8 ) e0161793 2016.08 [Refereed]

Stress granules (SGs) are cytoplasmic granular aggregations that are induced by cellular stress, including viral infection. SGs have opposing antiviral and proviral roles, which depend on virus species. The exact function of SGs during viral infection is not fully understood. Here, we showed that mumps virus (MuV) induced SGs depending on activation of protein kinase R (PKR). MuV infection strongly induced interferon (IFN)-lambda 1, 2 and 3, and IFN-beta through activation of IFN regulatory factor 3 (IRF3) via retinoic acid inducible gene-I (RIG-I) and the mitochondrial antiviral signaling (MAVS) pathway. MuV-induced IFNs were strongly upregulated in PKR-knockdown cells. MuV-induced SG formation was suppressed by knockdown of PKR and SG marker proteins, Ras-GTPase-activating protein SH3-domain-binding protein 1 and T-cell-restricted intracellular antigen-1, and significantly increased the levels of MuV-induced IFN-lambda 1. However, viral titer was not altered by suppression of SG formation. PKR was required for induction of SGs by MuV infection and regulated type III IFN (IFN-lambda 1) mRNA stability. MuV-induced SGs partly suppressed type III IFN production by MuV; however, the limited suppression was not sufficient to inhibit MuV replication in cell culture. Our results provide insight into the relationship between SGs and IFN production induced by MuV infection.

DOI

Measles Virus Genotype D Wild Strains Suppress Interferon-Stimulated Gene Expression More Potently than Laboratory Strains in SiHa Cells

Masaru Jinushi, Soh Yamamoto, Noriko Ogasawara, Hideki Nagano, Shin Hashimoto, Hiroyuki Tsutsumi, Tetsuo Himi, Shin-ichi Yokota

VIRAL IMMUNOLOGY ( MARY ANN LIEBERT, INC ) 29 ( 5 ) 296 - 306 2016.06 [Refereed]

Changes in interferon (IFN)-stimulated gene (ISG) expression in cells infected with measles virus (MeV), four wild strains (belonging to different genotypes), and the laboratory strain Edmonston were examined. ISGs [MxA, 2'-5'-oligoadenylate synthetase, and interferon regulatory factor-1] were upregulated in an MeV-infection- induced manner and in an IFN-induced manner. In MeV-infected SiHa cell lines, the MeV infection-induced expression levels were in the order of A>H1>D8>D5>D3. On the other hand, all infected cell lines abolished type I and III IFN-induced ISG expression. However, partial type II IFN-mediated induction was observed in the MeV-infected cells. The wild strain of genotype D3 was the most potent inhibitor of MeV infection-induced and IFN-induced ISG expression and generated the highest titer of infectious viral particles. Edmonston triggered the highest levels of MeV infection-induced ISG expression in SiHa cells and produced the lowest titer of infectious particles. Expression of the viral C protein was associated with suppression of MeV infection-induced and type II IFN-induced ISG expression.

DOI

Intrafamilial, Preferentially Mother-to-Child and Intraspousal, Helicobacter pylori Infection in Japan Determined by Mutilocus Sequence Typing and Random Amplified Polymorphic DNA Fingerprinting

Shin-ichi Yokota, Mutsuko Konno, Shin-ichi Fujiwara, Nariaki Toita, Michiko Takahashi, Soh Yamamoto, Noriko Ogasawara, Tsukasa Shiraishi

HELICOBACTER ( WILEY-BLACKWELL ) 20 ( 5 ) 334 - 342 2015.10 [Refereed]

Background: The infection route of Helicobacter pylori has been recognized to be mainly intrafamilial, preferentially mother-to-child, especially in developed countries. To determine the transmission route, we examined whether multilocus sequence typing (MLST) was useful for analysis of intrafamilial infection. The possibility of intraspousal infection was also evaluated. Materials and Methods: Clonal relationships between strains derived from 35 index Japanese pediatric patients, and their family members were analyzed by two genetic typing procedures, MLST and random amplified polymorphic DNA (RAPD) fingerprinting. Results: Mostly coincident results were obtained by MLST and RAPD. By MLST, the allele of loci in the isolates mostly matched between the index child and both the father and mother for 9 (25.7%) of the 35 patients, between the index child and the mother for 25 (60.0%) of the 35 patients. Conclusions: MLST is useful for analyzing the infection route of H. pylori as a highly reproducible method. Intrafamilial, especially mother-to-children and sibling, infection is the dominant transmission route. Intraspousal infection is also thought to occur in about a quarter in the Japanese families.

DOI

Geranylgeranylacetone selectively binds to the HSP70 of Helicobacter pylori and alters its coccoid morphology

Ewa Grave, Shin-ichi Yokota, Soh Yamamoto, Arisa Tamura, Takako Ohtaki-Mizoguchi, Kenji Yokota, Keiji Oguma, Kazuhiko Fujiwara, Nobuaki Ogawa, Tomoya Okamoto, Michiro Otaka, Hideaki Itoh

SCIENTIFIC REPORTS ( NATURE PUBLISHING GROUP ) 5 13738 2015.09 [Refereed]

Geranylgeranylacetone (GGA) is used to treat patients suffering from peptic ulcers and gastritis. We examined the effect of GGA on Helicobacter pylori, which is a causative factor of gastrointestinal diseases. Previously, we have reported that GGA binds specifically to the molecular chaperone HSP70. In this paper, we report that GGA bounds to H. pylori HSP70 (product of the DnaK gene) with 26-times higher affinity than to human HSP70, and induced large conformational changes as observed from surface plasmon resonance and circular dichroism. Binding of GGA suppressed the activity of the H. pylori chaperone. GGA also altered several characteristics of H. pylori cells. GGA-treated cells elicited enhanced interleukin-8 production by gastric cancer cell lines and potentiated susceptibility to complement as compared to untreated cells. GGA also caused morphological alterations in H. pylori as reflected in fewer coccoid-like cells, suggesting that GGA converts H. pylori to an actively dividing, spiral state (vegetative form) from a non-growing, coccoid state. This morphological conversion by GGA resulted in accelerated growth of H. pylori. These results suggest a model in which GGA sensitizes H. pylori to antibiotic treatment by converting the cells to an actively growing state.

DOI

扁桃・アデノイドはなぜあるのか?鼻はなにをしているのか? 粘膜免疫・粘膜防御の最前線を探る

氷見徹夫, 高野賢一, 山下恵司, 小笠原徳子, 山本圭佑, 堤裕幸, 小島隆, 一宮慎吾, 澤田典均, 横田伸一

顎顔面口腔育成会誌 ( 顎顔面口腔育成研究会 ) 3 ( 1 ) 3 - 6 2015.03

粘膜防御機構は自然免疫の最前線であり、上皮細胞に加えて免疫系細胞などを含む複合的なシステムで構築されている。耳鼻咽喉科領域では扁桃・アデノイドに代表される粘膜関連リンパ装置は、その抗原捕捉機構を駆使して、免疫記憶の形成と特異的抗体産生機構に関与している。一方、上気道の最前線である鼻粘膜もまた抗原捕捉に伴う免疫反応を行っているとともに、ウイルス・細菌感染やアレルギー炎症の場としても重要である。われわれは、扁桃やアデノイド、そして鼻粘膜の上皮についての研究を行い、機械的バリアを含む自然免疫の新しい概念を提唱してきた。ここでは、われわれの研究より得られた知見をもとに、扁桃、鼻粘膜の基本的な免疫臓器としての機能解析と、それぞれの類似性・相違性、自然免疫・獲得免疫での位置づけについて言及する。(著者抄録)

Isolation of Escherichia coli Strains with AcrAB-TolC Efflux Pump-Associated Intermediate Interpretation or Resistance to Fluoroquinolone, Chloramphenicol and Aminopenicillin from Dogs Admitted to a University Veterinary Hospital

Toyotaka Sato, Shin-ichi Yokota, Risa Ichihashi, Tomoka Miyauchi, Torahiko Okubo, Masaru Usui, Nobuhiro Fujii, Yutaka Tamura

JOURNAL OF VETERINARY MEDICAL SCIENCE ( JAPAN SOC VET SCI ) 76 ( 7 ) 937 - 945 2014.07 [Refereed]

Understanding the prevalence of antimicrobial-resistance and the relationship between emergence of resistant bacteria and clinical treatment can facilitate design of effective treatment strategies. We here examined antimicrobial susceptibilities of Escherichia coli isolated from dogs admitted to a university hospital (University hospital) and companion animal clinics (Community clinics) in the same city and investigated underlying multidrug-resistance mechanisms. The prevalence of E. coli with intermediate and resistant interpretations to ampicillin (AMP), enrofloxacin (ENR) and chloramphenicol (CHL) was higher in the University hospital than in the Community clinics cases. Use of antimicrobials, including fluoroquinolone, was also significantly higher in the University hospital than in the Community clinics cases. Upon isolation using EN R-supplemented agar plates, all EN R-resistant isolates had 3-4 nucleotide mutations that accompanied by amino acid substitutions in the quinolone-resistance-determining regions of gyrA, parC and parE, and 94.7% of all isolates derived from the University hospital showed AMP and/or CHL resistance and possessed bla(TEM) and/or catA1. The average niRNA expression levels of acrA, acrB and yo/C and the prevalence of organic solvent tolerance, in isolates derived from ENR-supplemented agar plates were significantly higher in the University hospital than in the Community clinics isolates. Thus, E. coli derived from the University hospital cases more often showed concomitant decreased susceptibilities to aminopenicillins, fluoroquinolones and CH L than did those derived from the Community clinics; this was related to an active AcrAB-ToIC efflux pump, in addition to acquisition of specific resistance genes and genetic mutations.

DOI

[Application possibility of the macrolides for the RS virus infections].

Yokota S, Tsutsumi H, Himi T

The Japanese journal of antibiotics ( 3 ) 67 147 - 155 2014.06 [Refereed]

PubMed

Association of Veterinary Third-Generation Cephalosporin Use with the Risk of Emergence of Extended-Spectrum-Cephalosporin Resistance in Escherichia coli from Dairy Cattle in Japan

Toyotaka Sato, Torahiko Okubo, Masaru Usui, Shin-ichi Yokota, Satoshi Izumiyama, Yutaka Tamura

PLOS ONE ( PUBLIC LIBRARY SCIENCE ) 9 ( 4 ) e96101 2014.04 [Refereed]

The use of extended-spectrum cephalosporins in food animals has been suggested to increase the risk of spread of Enterobacteriaceae carrying extended-spectrum b-lactamases to humans. However, evidence that selection of extended-spectrum cephalosporin-resistant bacteria owing to the actual veterinary use of these drugs according to criteria established in cattle has not been demonstrated. In this study, we investigated the natural occurrence of cephalosporin-resistant Escherichia coli in dairy cattle following clinical application of ceftiofur. E. coli isolates were obtained from rectal samples of treated and untreated cattle (n = 20/group) cultured on deoxycholate-hydrogen sulfide-lactose agar in the presence or absence of ceftiofur. Eleven cefazoline-resistant isolates were obtained from two of the ceftiofur-treated cattle; no cefazoline-resistant isolates were found in untreated cattle. The cefazoline-resistant isolates had mutations in the chromosomal ampC promoter region and remained susceptible to ceftiofur. Eighteen extended-spectrum cephalosporin-resistant isolates from two ceftiofur-treated cows were obtained on ceftiofur-supplemented agar; no extended-spectrum cephalosporin-resistant isolates were obtained from untreated cattle. These extended-spectrum cephalosporin-resistant isolates possessed plasmid-mediated beta-lactamase genes, including blaC(TX-M-2) (9 isolates), bla(CTX-M-14) (8 isolates), or bla(CMY-2) (1 isolate); isolates possessing bla(CTX-M-2) and bla(CTX-M-14) were clonally related. These genes were located on self-transmissible plasmids. Our results suggest that appropriate veterinary use of ceftiofur did not trigger growth extended-spectrum cephalosporin-resistant E. coli in the bovine rectal flora; however, ceftiofur selection in vitro suggested that additional ceftiofur exposure enhanced selection for specific extended-spectrum cephalosporin-resistant beta-lactamase-expressing E. coli clones

DOI

ATPase Activity and ATP-dependent Conformational Change in the Co-chaperone HSP70/HSP90-organizing Protein ( HOP)*

Soh Yamamoto, Ganesh Prasad Subedi, Shinya Hanashima, Tadashi Satoh, Michiro Otaka, Hideki Wakui, Ken-ichi Sawada, Shin-ichi Yokota, Yoshiki Yamaguchi, Hiroshi Kubota, Hideaki Itoh

JOURNAL OF BIOLOGICAL CHEMISTRY ( AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC ) 289 ( 14 ) 9880 - 9886 2014.04 [Refereed]

Background: HOP assists protein transfer in the HSP70- and HSP90-dependent protein-folding pathway. Results: HOP hydrolyzed ATP, and the region containing amino acids 1-359 (TPR1-TPR2A) was required for hydrolysis and direct interaction with ATP. Conclusion: HOP has slow ATPase activity and changes its conformation upon ATP hydrolysis. Significance: This is the first demonstration of the ATPase activity of HOP, and may enhance our understanding of the physiological function. Co-chaperones help to maintain cellular homeostasis by modulating the activities of molecular chaperones involved in protein quality control. The HSP70/HSP90-organizing protein (HOP) is a co-chaperone that cooperates with HSP70 and HSP90 in catalysis of protein folding and maturation in the cytosol. We show here that HOP has ATP-binding activity comparable to that of HSP70/HSP90, and that HOP slowly hydrolyzes ATP. Analysis of deletion mutants revealed that the ATPase domain of HOP is in the N-terminal TPR1-DP1-TPR2A segment. In addition, HOP changes its conformation in the presence of ATP. These results indicate that HOP is a unique co-chaperone that undergoes an ATP-dependent conformational change.

DOI

Comparison of broad-spectrum cephalosporin-resistant Escherichia coli isolated from dogs and humans in Hokkaido, Japan

Torahiko Okubo, Toyotaka Sato, Shin-ichi Yokota, Masaru Usui, Yutaka Tamura

JOURNAL OF INFECTION AND CHEMOTHERAPY ( SPRINGER JAPAN KK ) 20 ( 3-4 ) 243 - 249 2014.03 [Refereed]

Resistance to broad-spectrum cephalosporins (BSCs) in Enterobacteriaceae in companion animals has become a great concern for public health. To estimate the dissemination of BSC-resistant bacteria between dog and human, we examined the BSC-resistance determinants of and genetic similarities between 69 BSC-resistant Escherichia coli isolates derived from canine rectal swabs (n = 28) and human clinical samples (n = 41). Some E. coli isolates possessed bla(TEM-1b) (14 canine and 16 human isolates), bla(CTx-M-2) (6 human isolates), bla(CTx-M-14) (3 canine and 14 human isolates), bla(CTx-M-27) (1 canine and 15 human isolates), and bla(CMY-2) (11 canine and 3 human isolates). The possession of CTX-M-type beta-lactamases was significantly more frequent in human isolates, whereas CMY-2 was more common in canine isolates. Bacterial typing methods (phylogenetic typing, O-antigen serotyping, and pulsed-field gel electrophoresis) showed little clonal relationship between canine isolates and human isolates. Plasmid analysis and Southern blotting indicated that the plasmids encoding CMY-2 were similar among canine and human isolates. Based on the differences in the major beta-lactamase and the divergence of bacterial types between canine and human isolates, it seems that clonal dissemination of BSC-resistant E. coli between canines and humans is limited. The similarity of the CMY-2-encoding plasmid suggests that plasmid-mediated beta-lactamase gene transmission plays a role in interspecies diffusion of BSC-resistant E. coli between dog and human. (C) 2013, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

DOI

Serum heat shock protein 47 levels are elevated in acute interstitial pneumonia

Tomoyuki Kakugawa, Shin-ichi Yokota, Yuji Ishimatsu, Tomayoshi Hayashi, Shota Nakashima, Shintaro Hara, Noriho Sakamoto, Hiroshi Kubota, Mariko Mine, Yasuhiro Matsuoka, Hiroshi Mukae, Kazuhiro Nagata, Shigeru Kohno

BMC PULMONARY MEDICINE ( BIOMED CENTRAL LTD ) 14 48 2014.03 [Refereed]

Background: Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagen. We hypothesized that HSP47 could be a useful marker for fibrotic lung disease. The aim of this study was to evaluate serum levels of HSP47 in patients with various idiopathic interstitial pneumonias (IIPs). Methods: Subjects comprised 9 patients with acute interstitial pneumonia (AIP), 12 with cryptogenic organizing pneumonia (COP), 16 with nonspecific interstitial pneumonia (NSIP), 19 with idiopathic pulmonary fibrosis (IPF), and 19 healthy adult volunteers. Results: Patients with AIP had serum HSP47 levels that were significantly higher than those of COP, NSIP or IPF patients and those of healthy volunteers. In contrast, serum levels of HSP47 among patients with COP, NSIP, IPF, and healthy volunteers did not differ significantly. Receiver operating characteristic curves revealed that the cut-off level for HSP47 that resulted in the highest diagnostic accuracy for discriminating between AIP and COP, NSIP, IPF, and healthy controls was 859.3 pg/mL. The sensitivity, specificity, and diagnostic accuracy were 100.0%, 98.5%, and 98.7%, respectively. Conclusion: The present results demonstrate that, among patients with various IIPs, serum levels of HSP47 were elevated specifically in patients with AIP.

DOI

Phylogenetic association of fluoroquinolone and cephalosporin resistance of D-O1-ST648 Escherichia coli carrying bla(CMY-2) from faecal samples of dogs in Japan

Toyotaka Sato, Shin-ichi Yokota, Torahiko Okubo, Masaru Usui, Nobuhiro Fujii, Yutaka Tamura

JOURNAL OF MEDICAL MICROBIOLOGY ( SOC GENERAL MICROBIOLOGY ) 63 ( 2 ) 263 - 270 2014.02 [Refereed]

This study aimed to investigate the genetic association between fluoroquinolone (FQ) and/or cephalosporin (CEP) resistance in Escherichia coli isolates from dogs, and the risk to human health. We characterized E. coli clinical isolates, derived from faecal samples of dogs attending veterinary hospitals, using phylogenetic grouping, determination of virulence factor (VF) prevalence, multilocus sequence typing (MLST) and O serotyping. The D group was the dominant phylogenetic group among strains resistant to FQ and/or CEP. In contrast, the dominant group among susceptible strains was group B2. Group D strains showed a significantly higher prevalence of VFs than strains belonging to groups A and B1, and were resistant to significantly more antimicrobials than group B2 strains. The phylogenetic distribution of FQ CEP-resistant E. coli groups (FQ CEPRECs) and FQ-resistant groups was significantly correlated (r=0.98), but FQ CEPRECs and CEP-resistant E. coli groups were not correlated (r=0.58). Data from PFGE, 0 serotype and MLST analyses indicated that the majority of FQ-resistant strains derived from a particular lineage of phylogenetic group D: serotype 01 and sequence type (ST) 648. Some D-O1-ST648 strains carried bla(CMY-2), showed multidrug resistance and possessed a higher prevalence of the VFs kspMT, ompT and PAI compared with other group D strains. Our data indicate that the emergence of FQ-CEP-resistant E. coli is based primarily on FQ-resistant E. coli. Moreover, as strains of the D-O1-ST648 lineage have been found in clinical isolates derived from humans at a relatively high frequency, our findings indicate that the spreading of D-O1-ST648 strains may cause serious difficulties in both veterinary and human clinical fields in the future.

DOI

Aminoglycosides Suppress the Protein Folding Activity of the Molecular Chaperone HSC70: Implication of a Structure-Activity Relationship

Soh Yamamoto, Hideki Wakui, Hiroshi Kubota, Atsushi Kornatsuda, Hideaki Itoh, Shin-Ichi Yokota

CHEMOTHERAPY ( KARGER ) 60 ( 1 ) 37 - 46 2014 [Refereed]

Background: The mechanism of aminoglycoside (AG)-induced nephrotoxicity has not been fully elucidated. We previously reported that gentamicin suppresses the functions of HSC70, a heat shock cognate protein, which is a cytosolic molecular chaperone in mammalian cells. However, the relationship between HSC70 dysfunction and nephrotoxicity has not been clarified yet. Methods: The effects of 11 AGs, including gentamicin, on the function, protein refolding and substrate binding of HSC70 were examined in vitro. The protein refolding activity of HSC70 was examined by enzymatic activity restoration of the denatured firefly luciferase. Substrate binding activity of HSC70 was examined by the binding of fluorescent-dye-labeled reduced carboxymethlylated alpha-lactalbumin determined by HSC70/substrate complex formation by native polyacrylamide gel electrophoresis. Results: Strong inhibitory activity of AGs on the protein refolding activity of HSC70 was observed for arbekacin, gentamicin, neomycin and sisomicin, but not spectinomycin, streptomycin, ribostamycin and paromomycin, and inhibition was weak for tobramycin, amikacin and kanamycin. Neomycin strongly suppressed the formation of the HSC70/substrate complex and had the lowest concentration that resulted in 50% inhibition (IC50; in the order of 10(-4) nn). Arbekacin, gentamicin, sisomicin and tobramycin had IC50 values in the order of 10(-3) M. Amikacin, ribostamycin and paromomycin had no effective potencies. Conclusions: The inhibition efficacies of AGs for protein refolding of HSC70 were as follows: neomycin >> gentamicin, arbekacin, and sisomicin > tobramycin, amikacin and kanamycin > spectinomycin, streptomycin, ribostamycin and paromomycin. Amino groups and/or hydroxyl groups located at 2', 3',4', and 6' of amino sugar residue II, as well as the number of amino sugar rings were closely associated with the inhibition efficacies of AGs. Inhibition efficacies of AGs towards the function of HSC70 correlated well with the nephrotoxicity of AGs deduced from the in vivo studies previously reported. Amino groups/hydroxyl groups and the number of amino sugar rings of AGs were shown to be important for inhibition efficacies. The results strongly suggest that the AG-induced dysfunction of HSC70 is involved in the nephrotoxicity. (C) 2014 S. Karger AG, Basel

DOI

Characterization of a Lactobacillus gasseri JCM 1131(T) Lipoteichoic Acid with a Novel Glycolipid Anchor Structure (vol 79, pg 3315, 2013)

Tsukasa Shiraishi, Shin-ichi Yokota, Naoki Morita, Satoru Fukiya, Satoru Tomita, Naoto Tanaka, Sanae Okada, Atsushi Yokota

APPLIED AND ENVIRONMENTAL MICROBIOLOGY ( AMER SOC MICROBIOLOGY ) 79 ( 24 ) 7931 - 7931 2013.12 [Refereed]

DOI

Humulone suppresses replication of respiratory syncytial virus and release of IL-8 and RANTES in normal human nasal epithelial cells

Jun Fuchimoto, Takashi Kojima, Tamaki Okabayashi, Tomoyuki Masaki, Noriko Ogasawara, Kazufumi Obata, Kazuaki Nomura, Satoshi Hirakawa, Naoyuki Kobayashi, Tatsuro Shigyo, Shin-ichi Yokota, Nobuhiro Fujii, Hiroyuki Tsutsumi, Tetsuo Himi, Norimasa Sawada

MEDICAL MOLECULAR MORPHOLOGY ( SPRINGER JAPAN KK ) 46 ( 4 ) 203 - 209 2013.12 [Refereed]

Respiratory syncytial virus (RSV) is the major infectious agent causing serious respiratory tract inflammation in infants and young children. However, an effective vaccine and anti-viral therapy for RSV infection have not yet been developed. Hop-derived bitter acids have potent pharmacological effects on inflammation. Therefore, we investigated the effects of humulone, which is the main constituent of hop bitter acids, on the replication of RSV and release of the proinflammatory cytokine IL-8 and chemokine RANTES in RSV-infected human nasal epithelial cells (HNECs). We found that humulone prevented the expression of RSV/G-protein, formation of virus filaments and release of IL-8 and RANTES in a dose-dependent manner in RSV-infected HNECs. These findings suggest that humulone has protective effects against the replication of RSV, the virus assembly and the inflammatory responses in HNECs and that it is a useful biological product for the prevention and therapy for RSV infection.

DOI

Marked induction of matrix metalloproteinase-10 by respiratory syncytial virus infection in human nasal epithelial cells

Satoshi Hirakawa, Takashi Kojima, Kazufumi Obata, Tamaki Okabayashi, Shin-ichi Yokota, Kazuaki Nomura, Toshimasa Obonai, Jun Fuchimoto, Tetsuo Himi, Hiroyuki Tsutsumi, Norimasa Sawada

Journal of Medical Virology 85 ( 12 ) 2141 - 2150 2013.12 [Refereed]

Respiratory syncytial virus (RSV) is an important pathogen of bronchiolitis, asthma, and severe lower respiratory tract disease in infants and young children. Matrix metalloproteinases (MMPs) play key roles in viral infection, inflammation and remodeling of the airway. However, the roles and regulation of MMPs in human nasal epithelial cells (HNECs) after RSV infection remain unclear. To investigate the regulation of MMP induced after RSV infection in HNECs, an RSV-infected model of HNECs in vitro was used. It was found that mRNA of MMP-10 was markedly increased in HNECs after RSV infection, together with induction of mRNAs of MMP-1, -7, -9, and -19. The amount of MMP-10 released from HNECs was also increased in a time-dependent manner after RSV infection as was that of chemokine RANTES. The upregulation of MMP-10 in HNECs after RSV infection was prevented by inhibitors of NF-κB and pan-PKC with inhibition of RSV replication, whereas it was prevented by inhibitors of JAK/STAT, MAPK, and EGF receptors without inhibition of RSV replication. In lung tissue of an infant with severe RSV infection in which a few RSV antibody-positive macrophages were observed, MMP-10 was expressed at the apical side of the bronchial epithelial cells and alveolar epithelial cells. In conclusion, MMP-10 induced by RSV infection in HNECs is regulated via distinct signal transduction pathways with or without relation to RSV replication. MMP-10 may play an important role in the pathogenesis of RSV diseases and it has the potential to be a novel marker and therapeutic target for RSV infection. J. Med. Virol. 85:2141-2150, 2013. © 2013 Wiley Periodicals, Inc.

DOI PubMed

Serum heat shock protein 47 levels in patients with drug-induced lung disease.

Kakugawa T, Yokota S, Ishimatsu Y, Hayashi T, Nakashima S, Hara S, Sakamoto N, Matsuoka Y, Kubota H, Mine M, Mukae H, Nagata K, Kohno S

Respiratory research 14 133 2013.11 [Refereed]

DOI PubMed

Curcumin Prevents Replication of Respiratory Syncytial Virus and the Epithelial Responses to It in Human Nasal Epithelial Cells

Kazufumi Obata, Takashi Kojima, Tomoyuki Masaki, Tamaki Okabayashi, Shinichi Yokota, Satoshi Hirakawa, Kazuaki Nomura, Akira Takasawa, Masaki Murata, Satoshi Tanaka, Jun Fuchimoto, Nobuhiro Fujii, Hiroyuki Tsutsumi, Tetsuo Himi, Norimasa Sawada

PLoS ONE 8 ( 9 ) e70225 2013.09 [Refereed]

The human nasal epithelium is the first line of defense during respiratory virus infection. Respiratory syncytial virus (RSV) is the major cause of bronchitis, asthma and severe lower respiratory tract disease in infants and young children. We previously reported in human nasal epithelial cells (HNECs), the replication and budding of RSV and the epithelial responses, including release of proinflammatory cytokines and enhancement of the tight junctions, are in part regulated via an NF-κB pathway. In this study, we investigated the effects of the NF-κB in HNECs infected with RSV. Curcumin prevented the replication and budding of RSV and the epithelial responses to it without cytotoxicity. Furthermore, the upregulation of the epithelial barrier function caused by infection with RSV was enhanced by curcumin. Curcumin also has wide pharmacokinetic effects as an inhibitor of NF-κB, eIF-2α dephosphorylation, proteasome and COX2. RSV-infected HNECs were treated with the eIF-2α dephosphorylation blocker salubrinal and the proteasome inhibitor MG132, and inhibitors of COX1 and COX2. Treatment with salubrinal, MG132 and COX2 inhibitor, like curcumin, prevented the replication of RSV and the epithelial responses, and treatment with salubrinal and MG132 enhanced the upregulation of tight junction molecules induced by infection with RSV. These results suggest that curcumin can prevent the replication of RSV and the epithelial responses to it without cytotoxicity and may act as therapy for severe lower respiratory tract disease in infants and young children caused by RSV infection. © 2013 Obata et al.

DOI PubMed

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Papers - YOKOTA Shinichi